Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models

Abstract

Tubulointerstitial fibrosis is a hallmark feature of chronic renal injury. Specific therapies to control the progression of renal fibrosis toward end-stage renal failure are limited. Previous studies have demonstrated that expression of endogenous bone morphogenic protein-7 (BMP-7) is reduced in the kidneys of several inducible mouse models of acute and chronic renal disease and that administration of exogenous recombinant human BMP-7 (rhBMP-7) has a beneficial effect on kidney function. Here we report that treatment with rhBMP-7 leads to improved renal function, histology, and survival in mice deficient in the alpha3-chain of type IV collagen and MRL/MpJlpr/lpr lupus mice, two genetic models for chronic renal injury and fibrosis. Such therapeutic benefit is also associated with a significant decrease in the expression of profibrotic molecules, such as type I collagen and fibronectin, in renal fibroblasts. Additionally, rhBMP-7 induces expression of active matrix metalloproteinase-2, which is potentially important for removal of fibrotic matrix. Collectively, these studies provide further evidence for rhBMP-7 as an important bone-associated protein with protective function against renal pathology.

Bone Marrow–Derived Myofibroblasts Contribute to the Renal Interstitial Myofibroblast Population and Produce Procollagen I after Ischemia/Reperfusion in Rats

“…In this study, we observed an altered balance between BMP-7 and TGF-␤, two major regulators of renal interstitial fibrosis (28). Whereas TGF-␤ is a well-established inducer of fibrosis by stimulating differentiation to and proliferation of myofibroblasts (29,30), BMP-7 directly counteracts TGF-␤-induced ECM production and promotes epithelial differentiation (31,32). The transcriptional increase of TGF-␤ and decrease of BMP-7 may provide the environmental clues for preferential differentiation of BMDC toward myofibroblasts and subsequent production of ECM proteins.…”

Transcriptional Profiling Reveals Novel Markers of Liver Fibrogenesis

“…We showed induction of gremlin in activated human stellate cells and subsequently in the fibrotic livers of Mdr2(Ϫ/Ϫ) mice. Administrating bone morphogenic protein-7 inhibits the development of kidney fibrosis and may even reduce preexisting fibrosis in the kidney (37). This suggests that induction of gremlin may have a profibrotic effect, indicating that inhibition of gremlin expression could be beneficial for patients suffering from liver or kidney fibrosis.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…A large number of therapeutic options to interfere with TGF-bioactivity has been tested in preclinical studies including antagonistic antibodies, soluble receptor forms, agents that inhibit downstream intracellular signaling molecules (in particular Smads), RNA interference and targeting of TGF--induced micro-RNAs (20,255,(257)(258)(259)(260). Other antifibrotic interventions in the system are focused on modulators of TGF-bioactivity, such as BMP-7 or BMP antagonists such as USAG-1 (253,261,262). BMP7 receptor Alk3 (263), and its downstream mediator Trps1 (264), have also been shown to be involved in kidney fibrosis.…”